The phase I Sym004 study had 39 evaluable patients (median age mid to late 60s) with metastatic colorectal cancer and acquired EGFR inhibitor resistance who were enrolled into two dose cohorts. All had been previously treated with at least one course of anti-EGFR monoclonal antibodies and all had a documented response to EGFR inhibition followed by disease progression, reported Josep Tabernero, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, and colleagues.

Among all patients, 17 (44%) experienced some degree of tumor shrinkage while five patients (13%) achieved a partial response, including one found to harbor an EGFRS4a92R mutation, which is predictive of cetuximab resistance, the authors wrote in Cancer Discovery.

"Patients with advanced colorectal tumors without mutations in the RAS genes derive substantial benefit from anti-EGFR therapies," Tabernero stated in an accompanying press release. "However, the disease eventually progresses, leaving these patients with few alternative therapeutic options."

The Sym004 trial offered a new treatment option in these patients. Directed against non-overlapping EGFR epitopes, Sym004 consists of two recombinant, human-mouse chimeric monoclonal antibodies. In preclinical models, it caused significant EGFR internalization and degradation via cross-linking, which translated into superior growth inhibition in the presence of EGFR ligands, the investigators explained. Pharmacodynamic studies have confirmed marked Sym004-induced down-modulation of EGFR.

Trial Details

Patients were enrolled from 2010 to 2012 in two Sym004 dose-expansion cohorts of 9 mg/kg and 12 mg/kg weekly.

Among the 17 patients who experienced some degree of tumor shrinkage, four of 12 and 13 of 27 had received doses of 9 mg/kg and 12 mg/kg, respectively. The overall disease control rate (partial response and stable disease) was 67% (58% for 9 mg/kg and and 70% for 12 mg/kg).

The three patients with KRAS mutations at baseline had stable disease with PFS of 2.6, 4.8, and 7.1 months, respectively.

Adverse events of any grade were reported in 61 patients, with the most common drug-related adverse events of any grade being skin rash (69%), dry skin (45%), hypomagnesemia (53%), pruritus (39%), mucosal inflammation (31%), and diarrhea (27%). Grade 3 or higher adverse events affected more patients in the 12-mg/kg group (50% versus 21%), and one drug-related death occurred at this dose. More patients on the higher dose reduced or interrupted their therapy.

These encouraging results support targeted monotherapy in this refractory patient population -- those with tumors the authors described as "EGFR-addicted."

While acknowledging the limited number of patients treated, the authors pointed out that "it remains noteworthy that the response rate seen in this trial was similar to that assessed in previous phase III studies with cetuximab and panitumumab monotherapy in EGFR treatment-naive patients with metastatic colorectal cancer."

They added that unlike Sym004, cetuximab and panitumumab monotherapy has shown no clinically relevant activity in patients resistant to previous anti-EGFR monoclonal antibodies.

Sym004's demonstrated clinical anti-tumor activity "validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling," they wrote. "The disease control achieved with Sym004 in 26 of 39 patients in the acquired resistance setting forms a robust clinical basis to be tested in future trials."

Several trials are now underway to investigate the optimal dose and dosing schedule in this patient population, they added.

'Intriguing,' but More Data Needed

Celina Ang, MD, assistant professor of medicine and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City told MedPage Today that "the results from this study are intriguing and highlight a potential new option for patients with metastatic colorectal cancer that has progressed on anti-EGFR therapy, addressing a currently unmet need."

However Ang, who was not involved in the study, added that the findings need confirmation in later-phase clinical trials before Sym004 can be implemented in clinical practice.

"We also need additional studies to better define the molecular subpopulations who are most likely to benefit from Sym004," she said.

While noting that the side effect profile of Sym004 was similar to that of panitumumab and cetuximab, Ang cautioned that the incidence of grade 3 hypomagnesemia and skin toxicity in the trial was higher.

"While not necessarily prohibitive, these will require close monitoring and proactive supportive management, especially in patients who have been heavily pretreated," she said. Ang also pointed to the need to identify predictive biomarkers of response to enrich the patient population most likely to benefit from Sym004 and improve the cost-effectiveness of treatment.

Richard Schilsky, MD, chief medical officer of the American Society of Clinical Oncology, told MedPage Today that the interesting findings show that "some colorectal cancers become resistant to anti-EGFR antibody treatment by expressing high levels of the ligands that normally bind to these receptors, thus effectively competing with the antibodies."

"This antibody combination seems to overcome this mechanism of resistance by moving the receptors inside the cell leading to their degradation so they cannot be stimulated by the high ligand levels," said Schilsky.

"Unfortunately, this antibody combination does not appear to overcome the most common resistance mechanism to anti-EGFR antibodies, that is, mutation in the KRAS and NRAS genes downstream of EGFR that keep the pathway active even if the receptor is inhibited," he cautioned.

Measuring levels of EGFR ligand expression in tumors to see whether they correlated with response might have helped validate the authors' hypothesis and possibly identify a biomarker of response to treatment, he added.

With respect to the response rate of the study, the results are comparable to those seen when single-agent cetuximab was introduced in the clinic and given to patients not selected on the basis of RAS mutation testing, Schilsky said.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.